DE3137125A1 - USE OF PYRIDOXIN (ALPHA) KETOGLUTARATE FOR THE PROPHYLAXIS OF HYPERLACTACIDAEMIA - Google Patents

Description

T 52 902 ^

Applicant: ISTITUTO LUSO FARMACO D ¹ ITALIA S.ρ.Α., Via Carnia 26, Milan / Italy

Use of pyridoxine-cc-ketoglutarate for the prophylaxis of hyperlactacidemia

The invention relates to the use of pyridoxine a-ketoglutarate for the prophylaxis of hyperlactacidemia, it concerns in particular pharmaceutical agents and solid or liquid animal feed preparations suitable therefor;

Pyridoxine-cc-ketoglutarate (hereinafter abbreviated as "PAK" referred to) and its use as a detoxicant against isoniazid in the treatment of ammonium chloride caused hyperamroniaemia as a substance protecting the liver against carbon tetrachloride are already known from French patent 6 353 M; This patent also refers to in vitro metabolic activity pointed out - according to the oxygen consumption, measured using a Warbürg apparatus, with homogenized Liver and homogenized brain is significantly higher than that - which is caused by α-Ke to glutaric acid or caused by pyridoxine alone; Finally, this patent also refers to liver regenerative activity as well as a eutrophic activity of the PAH. * According to this patent, the concern Metabolic properties of the PAH the liver and the brain;

The PAH and its derivatives ^ which correspond to the following formula:

CH ₂ OH

.CH ₂ OH

-0OC-CO-CH ₉ -Ch ₉ -COOX

where X can mean a hydrogen atom or an alkali metal or alkaline earth metal or an organic base, ¹ are the subject of the German Offenlegungsschrift 19 58 226 According to the information therein, PAHs and their derivatives are therapeutically valuable drugs according to the above formula, - because they are within a single molecule both the pyridoxine and the oc-ketoglutarate unite with each other - leading to an increase in beneficial activities of these two compounds, and in certain cases to a reduction in toxicity of the same leads i According to the German patent application 19 58 226 have PAK and its derivatives have an activity (effectiveness) on the nervous system and they are therefore used in various neurological conditions due to the fact that they act on the brain metabolism as mediators in the following four important areas:
(a) as a substrate in breathing;

(b) as a transaminant for γ-aminobutyric acid (GABA) j

(c) as a prosthetic group of a special decarboxylase / converting glutamic acid into γ-aminobutyric acid

«7

delt, and
(d) as a NEW acceptor in detoxification processes;

According to the information in the above-mentioned German Offenlegungsschrift is based on these multiple metabolic activities the phannacological activity of PAHs valuable for the treatment of the following syndromes:

- Nerve metabolism deficiency symptoms;

- Tremor of various origins (age tremor, idiopathic

shear tremor, Parkinson's tremor) j

- convulsions in newborns;

- nervous disorders treated with isoniazid;

- Disturbances in neuromuscular processes (in this context it should be pointed out that in this field further research is needed); and

- acute alcoholism

PAK also shows:

«An anabolic activity (notable influence on protein synthesis, ¹ as it plays an important role in intermediate amino acid metabolism; as a result of this activity it is suggested that PAH is a non-hormonal anabolic drug useful for the treatment of diseases, related to anorexia or possible weight loss, ¹ convalescences, as thenia and

- an activity on fatty acid metabolism (after the DE-OS 19 58 226 there is a not yet fully clarified relationship between PAH and arteriosclerosis);

- an activity on blood formation (as a result of its anti-anemic Properties);

- an activity on the Kleber coma and precoma (as PAHs can bind ammonia);

Other indications are the following:

According to DE-OS 19 58 226 there are other indications - due which one could assume - that PAK can also be used in other cases, for example in gastrohemaemesis (especially with Haematoamesis gravidorum); for the treatment of some skin diseases (eczema, seborrheic Dermatitis, angulus infectiosus) j in deficiency disorders, - such as Zi'Bi * Beri-Beri and Pellagra; in HerzerkimkiHigen who did not respond to the usual therapy speak to;

It should be noted, however, · that all of these conjectures with very little or no clinical data to support therapeutic activity, see that the information on this multiple therapeutic activity at least still need to be verified;

It has now been found that the administration of PAK is particularly effective against the occurrence of hyperlactacidemia;

It is known that hyperlactacidemia causes a change the acid-base balance with a resulting more or less severe acidosisy die can possibly lead to a coma, leads

j] 3 / I e.g.

The main objective of the present invention is therefore to use PAK for the prophylaxis of Hyperlactacidämie in all the physiological and pathological situations, which are known, ^T that a hyperlactacidämischer condition can occur ^one or maintained by this condition, ^one and all those pathological cases ¹ for the therapy of which drugs are administered which lead to an increase in the blood lactic acid level, both in human medicine and in veterinary medicine,

Another object of the present invention is to provide pharmaceutical agents or; To find preparations which contain PAHs as active ingredients for the prophylaxis of the above-mentioned pathological conditions together with suitable non-toxic, pharmaceutically inert carriers or auxiliary substances; The aim of the invention is also to provide ¹ a method for the production of these pharmaceutical agents or; Indicate preparations;

Another object of the invention is to provide pharmaceutical agents or; Preparations in a dosage unit form suitable for the desired type of administration, ¹ for example in the form of vials for parenteral use, in the form of ampoules for oral use and in the form of tablets, - in which the content of the active ingredient (PAH) is a Corresponds to a fraction or a multiple of the single dose; The dose units can contain, for example, 1, 2, 3 or more up to 20 single doses or 1/2 ^ 1/3 or 1/4 of a single dose;

As can be seen from the above, ¹ PAH is already known; Up to now, however, it was not known that PAH is useful for the prophylaxis of all those physiological conditions of which it is known - that a hyperlactacidic condition can occur or that are maintained by this condition, as well as of all those pathological cases - for them Therapy Medicines are administered which cause an increase in the blood lactic acid level, both in human and in veterinary medicine;

The expression "non-toxic, inert, pharmaceutically acceptable carriers or auxiliaries" used here is to be understood as meaning solid or liquid diluting or encapsulating fillers; Some examples of such materials, to which the invention is not limited, are sugars such as lactose, glucose and sucrose; Starches, such as corn and potato starch ^, · cellulose and its derivatives, ^ as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate ^1; Powdery gum tragacanth; Malt, gelatin; Talc5 magnesium stearate, calcium sulfate; Polyols such as propylene glycol, ¹ glycerine, ¹ sorbitol, -, mannitol and polyethylene glycol; Agar Agar; Alginic acids; pyrogenic water; isotonic saline solutions and buffer solutions with a neutral or weakly acidic pH value as well as other non-toxic and tolerable materials, - which are usually used in the pharmaceutical industry for the production of pharmaceutical agents or preparations; In addition, wetting agents and lubricants, such as. B; Sodium lauryl sulphate, and coloring agents, - flavoring agents and possibly preservatives, - be present;

313712S

In the manufacture of the aforementioned pharmaceutical agents or preparations must always be taken into account, -that the pH of the PAH / carrier mixture must never exceed 7 i

The pharmaceutical preparations for the administration of PAHs according to the present invention are preferably in the form of vials for parenteral use (either iinü or iiVi) * ¹ in the form of ampoules for oral use, - in the form of syrups or tablets *

According to the invention, the daily dose for an adult vary from about 600 to about 9200 mg, preferably from 900 to 4600 mg; When PAK is administered in tablet form is, preferably 1 to 2 tablets are administered two to three times a day; if it is in the form of a syrup is administered, preferably one teaspoon of PAK administered two to three times a day; when the administration of ampoules for oral use is required - 1 to 3 small bottles (ampoules) are preferably administered per day

According to the invention are for parenteral administration 1 to 3 vials a day are preferred Case of intravenous infusion 5 to 20 vials daily in 250 to 500 ml of a saline solution or other Solution, which is suitable for this purpose, administered. It should be noted that - the vials of PAK never with bicarbonate solutions or another material

40 ''

should be diluted with a pH value of more than 7 Acute toxicity data (UO ₅₀ - mg / kg)

(a) rat - PiOi 4800 - piOi - iimi 2329 - iimi ' - iipi 17Q4 - iipi -XiVi 588 • - iiVi ' Rabbits (b) mouse 5600 2472 1590 496 - (c)

1050

Chronic toxicity data

The administration of 400 mg / kg / piOi to rats for a period of 6 months did not lead to any side effects or toxic effects in the various organs} ¹

Systemic compatibility

The administration of 46 mg / kg / iiVi and 460 mg / kg / iiim in rats and 920 mg / kg / iinu in dogs is well tolerated

44 '

Influence on pregnancy

In pregnant rabbits and rats, oral administration of 1300 mg / kg and 46 mg / kg / iinu did not cause any harmful effects Effects in the pregnant female animal, - in gestation. and in the development of the fetus;

The production of the pharmaceutical agents (preparations) according to the invention is described in more detail in the following examples explains, but is not limited to, these examples explain the currently preferred manufacturing process, ^ however, it is self-evident for the person skilled in the art, that the invention is not limited to it, - but that there are many other, - equally effective ways of manufacturing of the pharmaceutical agents or preparations according to the invention are available

example 1 Vials for parenteral use composition

Pyridoxine-oc-ketoglutarate 460 mg

Water for an injectable

Preparation. ad 5 ml

Manufacturing

The operations were carried out in a sterile department; In one with a sterilizing millipore filter equipped dissolution device made of stainless Steel was dissolved in water for the manufacture of injectable PAHs Preparations; The filtered solution was dispensed using an automatic ampoule dispenser

Al

and dispensed into vials by adjusting the dosage to 5 ml;

Example 2 Ampoules for oral use Composition for a 10 ml ampoule

PAK 0, -5 S. Sorbitol solution 2.00 G Methyl p-hydroxybenzoate 0.008 G Propyl p-hydroxybenzoate 0, Ό04 G Na tr iumed e ta t ^ 0.0025 G Sweet orange essence 0.001 G Lemon essence 0.0001 G Sucrose 4.0 G purified water ad 10 ml

Manufacturing

The purified water and the sorbitol solution were introduced into a stainless steel reaction vessel, - it was heated to 75 ° G and sucrose, - methyl p-hydroxybenzoate and propyl p-hydroxybenzoate were added with stirring; then the mixture was heated to 105 ° C. and held at this temperature for 5 minutes; The whole thing was cooled to 30 C and the sodium edetate, the pyridoxine-a-ketoglutarate (PAK) _s - the sweet orange essence and the lemon essence were added; The filtered syrup was dosed into small bottles using an automatic filler;

⁺ 'Sodium salt of ethylenediaminetetraacetic acid

■ i -.-- --- -. -ο IJ / lzb

1h

5 G G G G G 20.00 G ad 100 ml 0, Ό8 G 0.04 G 0.025 0, ol Ο, ΌΟΙ 40.00

Example 3

Syrup ;

Composition for 100 ml

PAK

Sorbitol solution Methyl p-hydroxybenzoate propyl p-hydroxybenzoate Sodium edetate Sweet orange essence Lemon essence Sucrose

Purified water

Manufacturing

The purified water and the sorbitol solution were put in a reaction vessel made of stainless steel - then it was heated to 75 C and with stirring the sucrose, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate admitted; then the mixture was heated to 105 ° C. and held at this temperature for 5 minutes; It was cooled to 30 C and the sodium edetate, 'the pyridoxine-a-ketoglutarate, -die sweet orange essence and the lemon essence were added. The filtered syrup was using an automatic dosing device in small bottles filled;

Example 4

Tablets

Composition for .each tablet

PAH 300 mg

- * ζ ": ι ι 3137125 Polyvinyl pyrrolidone 15 mg Stearic acid 14 mg Talk 25 mg Hydroxypropyl cellulose 4 mg Titanium dioxide 2 mg Manufacturing

The PAH was granulated with a water polyvinylpyrrolidone solution; After the granules had dried, the Stearic acid and the talc added and mixed; The mixture obtained in this way is rotated in a rotary device pressed with punches with a diameter of 9 mm for the production of tablets with a weight from 351 mg per tablet; The tablets were then coated with a film by spraying on a methylene chloride / ethanol suspension in front of hydroxypropyl cellulose, talc and titanium dioxide in a Glatt WSG 60 Wuster apparatus;

Prophylactic effect of PAHs against the development of hyperlactacidemia

(A) It is known that administration of metformin leads to lactic acidosis in rats. Administration of PAK (25 mg / hour by infusion into the vein) to male Wistar rats weighing 200 to 220 g that have fasted for hours resulted in a marked decrease in lactic acidemia both when PAK was concomitantly with Metformin (300 mg / i; d;) is administered (modality ' ¹ A ") as well as when it is administered three hours later (modality" B ¹¹ ); The lactad levels obtained in this way are for modality ¹¹ A ″ 2.9 + 0.8 mM / 1 or 1.37 +

if.

0, -01 mM / 1 with the modality "B" i

The comparison animals have a lactacidemia value of 5.1 + 0.59 mM / 1. '

The drug therefore prevents the biguanide caused Hyperlactacidemia;

(B) PAH is administered to 14 insulin-dependent patients, to determine whether the medicine is capable of the Increase in lactic acid in plasma after muscle exercise to control;

All patients are treated with insulin and lie in metabolic compensation;

The experiments are carried out under double-blind conditions. Every patient is subjected to an isometric stress test at 50% of its maximum capacity for one minute. The test is performed after a vein infusion of 250 ml of a physiological solution or a solution of pyridoxine-a-ketoglutarate (2300 mg of active substance in 250 ml of a physiological solution) carried out on the same patient i

The samples for determining lacticemia are taken from the taken from the same arm with which the muscle exercise is carried out *

Between the administrations of the two preparations, ie; the

physiological solution or the PAH solution, is a free time of 1/2 hour, - during the physiological Solution is administered.

The mean values for lactic acidemia are as follows:

(a) order of treatment; Physiological solution / PAK Ii Physiological solution

- Basal 0.88 + 0.19

- Immediately after use 3.12 £ 0.46

- after 10 minutes 1.73 + 0.35

- after 15 minutes 1.54 + 0.30

2; PAK

- Basal 0.95 + 0.20

- Immediately after exposure to 2.62 + 0.38

- after 10 minutes 1. -60 +0.30

- after 15 minutes 1.18 + 0.30

(b) order of treatment; PAK / Physiological solution Ii PAK ■.

- Basal 0.88 + 0.16

- immediately after exposure 2.03 + _ 0.47

- after 10 minutes 1.30 + 0.33

- after 15 minutes 1, ¹ Il + 0.29

2i Physiological solution

- Basal. 0.93 + 0.19

- immediately after exposure 2.08 + _ 0.49

- after 10 minutes 1.43 + _ 0.44

- after 15 minutes 1.25 + 0.40

The analysis of the variance shows the following:

(a) The exercise leads to a statistically meaningful increase (p <0.01) in lactic acidemia j.

(b) by administration of PAHs the increase is (p <^ 0.0l) lower, based on the physiological solution;

(c) the decrease in lactacidemia occurs more rapidly with PAKj

(d) the effect of PAHs is delayed in time (in length drawn)

The PAH thus acts in the development of hyperlactacidemia as a result of stresses.

(C) Seven diabetic non-insulin dependent patients become mil for 7 days; Sulphanylurea at a therapeutic dose and an additional 7 days with sulphanylurea fen combined with PAH at a dosage of 1, -8 g / day / oiSi tested

The resulting lactic acid concentration in the blood is significantly lower in 5 of the 7 patients after administration of the combination; The average values of the Lactacidemia in these patients are as follows:

(a) After the administration of SuIfany! ureas: 2, -46 inM / i,

(b) after administration of sulfanylureas and PAHs: 1.16 mM / 1

The difference is statistically significant (ρ 4. O, 01) and the decrease in lactic acid concentration is 52.8%;

(D) By administering 30 mg / kg body weight PAH

on trained, non-athletic people, the maximum air utilization capacity (V _n max) increases by 6% (p <0.005),

^U 2
The kinetic values of the V _n -initial and final response-

^U 2
sensitivities at the beginning and end of a rectangular workload are not influenced by the drug; The peak lactam concentration in the blood [La,] after two supratnaximal running loads, which last 60 seconds or 132 + 4 seconds, - is significantly (p <0.05 and p <0.01) lower after the PAH treatment C ^ La, = -1.1 or -2.7 idM il " ) than that of the control group; the half-life (t 1/2) of La disappearance from the blood during recovery is not influenced by PAHs (19.7 minutes compared to 19, 5 minutes); from this it can be concluded that PAHs probably promote aerobic metabolism- ~ .. borrowed by activating the malate oxalate acetate conversion (shuttle) and by generating high-energy phosphates in the substrate; ·

(E) Administration of pyridoxine cc-ketoglutarate in the Vein (2300 mg in 250 ml of a physiological solution) of 25 kyrrhotic patients with hyperlactacidemia prevents the further increase and leads to a statistically significant (p-COjOl) decrease in this hyperlactacidemia, -related to the base values and related to the controls; Lactacidemia changes in those treated with PAK

Group actually from 22.71 + 1, -07 mg% to 15.99 + 0.73 mg% (ρ ^ 0.01), while with the physiological Solution treated group they differ from 21.50 + 0.85 mg% changes to 24.72 + 0.89 mg% (p <0.05). The difference between the active drug and the physiological solution is significant (p <0.01) i the tests were taking Performed double-blind conditions.

(F) For use in veterinary medicine, PAK feed or Feed premix preparations in effective, but not * toxic quantities incorporated · These preparations are then applied to animals, - especially horses, as indicated below fed.

According to the invention, the most frequently used feed pad is bran, oats, dry fodder, roughage, such as e.g. Silage or various commercially available grain mixtures - as they are usually used for animals. The amount of PAHs used to supplement this food pad is an amount * which is sufficient to reduce the stress caused by the hyperlactacidemia here to counteract, - which, however, has no toxic or otherwise harmful influence

When PAH was administered at a dose of 2 g / 100 kg weight / day for a period of 15 days to 5 trotters ¹ who are exposed to muscle strain (trot), a significant decrease in the formation of blood lactic acid is observed *

Namely, the lactacidemia before the treatment under the basic conditions is 6.04 mg / 100 ml and immediately after the exposure it rises to 29, -41 mg / 100 ml After the treatment the basic lactacidemia is 3.30 mg / 100 ml and immediately after exposure it is 15.94 mg / 100

Claims (1)

T 52 902 '' Applicant; ISTITUTO LUSO FARIlACO D ¹ ITALIA SpΑ., Via Carnia 26 , Milan / Italy Claims II Use of pyridoxine cc-ketoglutarate for prophylaxis all those physiological and pathological conditions which are known to be hyperlacta cidemic Condition occurred, as well as all those pathological cases for whose therapy drugs were administered - which cause an increase in the blood lactic acid level, both in human and veterinary «medicine» 2; A pharmaceutical composition for the prophylaxis of Hyperlactacidämie, characterized in that it comprises a pharmacologically effective amount l'yridoxin-a-ketoglutarate, together with usual non-toxic, inert ^1, contain pharmaceutically acceptable carriers ode :: adjuvants; 3; Pharmaceutical agent according to claim 2, - characterized in that that there is about 300 to about 500 mg of pyridoxine cc-ketoglutarate contains; 4i 'Process for the production of a pharmaceutical agent according to Claim 2 or 3, · »characterized in: that one pyridoxine-cc-ketoglutarate with non-toxic, - inert, Mixes pharmaceutically acceptable carriers or excipients. 5; Solid or liquid animal feed preparation for prophylaxis hyperlactacidemia, * characterized by that he has an effective, but non-toxic, amount of pyridoxine-a-ketoglutarate contains evenly dispersed or dissolved in the feed pad « 6i Process for the production of the solid or .liquid Animal feed preparation according to Claim 5, · characterized in that an effective, but non-toxic Mixing amount of pyridoxine-a-ketoglutarate with carriers and / or additives commonly used for animal feed;